Gas1 is related to the glial cell-derived neurotrophic factor family receptors alpha and regulates Ret signaling

J Biol Chem. 2006 May 19;281(20):14330-9. doi: 10.1074/jbc.M509572200. Epub 2006 Mar 20.

Abstract

The growth arrest-specific gene 1 (Gas1) protein has been proposed to function during development as an inhibitor of growth and a mediator of cell death and is also re-expressed in adult neurons during excitotoxic insult. Here we have demonstrated that the Gas1 protein shows high structural similarity to the glial cell-derived neurotrophic factor (GDNF) family receptors alpha, which mediate GDNF responses through the receptor tyrosine kinase Ret. We found that Gas1 binds Ret in a ligand-independent manner and sequesters Ret in lipid rafts. Signaling downstream of Ret is thus modified through a mechanism that involves the adaptor protein Shc as well as ERK, eventually blocking Akt activation. Consequently, when Gas1 is induced, Ret-mediated GDNF-dependent survival effects are compromised.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology*
  • DNA-Binding Proteins / metabolism*
  • GPI-Linked Proteins
  • Glial Cell Line-Derived Neurotrophic Factors / metabolism*
  • Humans
  • Lipids / chemistry
  • Membrane Microdomains / chemistry
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Proteins / metabolism*
  • Plasmids / metabolism
  • Rats
  • Sequence Homology, Amino Acid
  • Signal Transduction

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • GAS1 protein, human
  • GPI-Linked Proteins
  • Glial Cell Line-Derived Neurotrophic Factors
  • Lipids
  • Membrane Proteins
  • Nuclear Proteins
  • TRIM27 protein, human